1. Extensive Second-line Drug Resistance in Tuberculosis - “XDR TB”: Global Survey of Supranational TB Reference Laboratories Sarita Shah 1, Abigail Wright A 2, Fadila Boulahbal 3, Chris Gilpin 3, Francis Drobniewski 3, Gill-Han Bai 3, Marta Havelková 3, Rosario Lepe 3, Beverly Metchock 3, Maria Filomena Rodrigues 3, Françoise Portaels 3, Armand Van Deun 3, Sabine Rüsch-Gerdes 3, Véronique Vincent 3, Lucia Barrera 3, Kayla Laserson 1, Charles Wells 1, Peter Cegielski 1 1 CDC Atlanta, 2 WHO Geneva, 3 Supranational TB Reference Laboratory Network

2. Green Light Committee (GLC) evaluates and monitors DOTS-Plus projects world wide, ~60 to date, 35 approved in 29 countries, ~12,000 patients Increasing anecdotal reports of TB resistant to virtually all 2 nd -line drugs (SLDs) Informal consultation with several Supranational TB Reference Laboratory (SRL) directors –Confirmed similar observations –Supported a collaborative project to count these cases Background

3. Collaboration with WHO and SRL network to count cases of TB with extensive resistance to SLDs –Reputation of SRLs minimize questions of validity of 2 nd -line DST results –Global geographic distribution –Many SRLs are (national) reference labs (NRLs) in their own countries –In addition to QA for global DRS, many SRLs assist NRLs world wide –SRLs history of working together Proposal (mid-2005)

4. Objective To assess the extent to which extensive resistance to SLDs has begun to emerge among MDR Mycobacterium tuberculosis (Mtb) isolates in the SRL network

5. “XDR TB” defined as MDR TB that also has resistance to ≥3 of 6 major classes of SLDs (tested) All SRLs invited to contribute data on Mtb isolates tested for resistance to at least 3 major classes of SLDs, 2000-2004 17 of 23 SRLs agreed to participate, 12 sent data in time for 2005 IUATLD SLD resistance patterns analyzed by year, region, and 1 st line drug resistance pattern Methods

6. Study Sample Isolates submitted by SRLs (N=18,215) Isolates tested for >3 SLD classes (N=17,459) Tested for <3 SLD classes (N=535) Tested before 2000 (N=207) or Tested in 2005 (N=14) Isolates tested 2000 – 2004 (N=17,994)

7. Geographic region from which cultures were received by SRLs (N=17,459) Sub-saharan Africa317 (1.8%) North Africa + Middle East348 (2.0%) Asia (except S. Korea)381 (2.2%) UK + Western Europe511 (2.9%) Eastern Europe529 (3.0%) Russia624 (3.6%) Latin America985 (5.6%) North America1,767 (10.1%) Asia (S. Korea)11,939 (68.4%) TOTAL17,459 (100%)

8. First-line Drug Resistance Patterns 11 SRLs N (%) S. Korea N (%) Total number tested Any resistance Monoresistance Multidrug resistance Polyresist. non-MDR 5,520 3,594 (65) 790 (14) 2,163 (39) 1,629 (30) 11,939 2,508 (21) 952 (8) 1,298 (11) 329 (3) * Any except RIF

9. Prevalence of Resistance to 2 nd -line Drugs (isolates tested for at least 3 SLDs, %) any resistance to…MDR isolates N=3,461 Other Poly-R N=3,576 Amikacin or Kanamycin (AG) Capreomycin (CM) Ciprofloxacin or Ofloxacin (FQ) Ethio/prothionamide (TA) Cycloserine (CYS) PAS 18.1 8.0 19.3 17.4 14.1 12.9 17.7 7.7 18.3 17.6 3.9 14.0

10. ...among isolates tested for at least 3 SLDs, % MDR isolates N=3,461 Other Poly N=3,576 AG+CM AG+FQ AG+ >1 Group 4 drug CM+FQ CM+ >1 Group 4 drug FQ+ >1 Group 4 drug 7.2 6.1 7.6 3.1 4.0 11.3 7.0 6.4 8.2 3.0 3.9 11.1 AG+CM+FQ AG+CM+ >1 Group 4 drug AG+CM+FQ + >1 Group 4 Any 3 SLD classes 2.5 3.3 1.6 9.9 2.5 3.4 1.6 10.1 2nd-line Drug Resistance Patterns

11. Prevalence Second-line Drug Resistance By Geographic Region (%) Latin America 985 Sub-S. Africa 317 North America 1,771 West. Europe 511 Russia / E. Euro 1,153 N. Afr. Mid.E 348 Asia 12,316 1 st line Any Mono Multi Poly SLDs AG FQ CAP TA CYS PAS 72 9.4 55 41 19.6 8.0 3.9 13.5 1.1 5.6 34 10 19 11 1.3 0.6 0.9 5.4 0.9 0.6 63 26 18 13 2.1 3.2 1.4 4.9 0.3 2.3 99 2.4 88 59 6.8 10.8 4.7 24.3 5.3 7.8 61 13 35 32 16.6 4.2 8.5 9.9 1.3 8.5 36 5.7 27 25 2.9 0.6 0.9 5.2 0.6 0 23 7.9 13 4.2 1.9 4.6 1.0 2.5 0.7 3.4

12. Patterns of Second-line Drug Resistance in MDR Isolates by Geographic Region (N=3,461) Latin America 543 (%) N Amer 320 (%) UK / W Euro 451 (%) Russia / E Euro 406 (%) N Afr Mid E 95 (%) Asia 1,563 (%) AG+CM AG+FQ AG+ >1 Group 4 CM+FQ CM+ >1 Group 4 FQ+ >1 Group 4 drug AG+CM+FQ AG+CM+ >1 Group 4 AG+CM+FQ+1 Grp 4 Any 3 SLD classes 6.6 6.1 6.6 1.8 2.2 5.0 1.8 2.2 0.9 5.9 6.2 3.1 5.3 2.2 4.1 4.7 2.2 4.1 2.2 4.7 4.0 5.8 2.4 3.5 9.3 1.5 2.7 1.3 7.8 20.9 5.7 17.7 1.2 7.6 6.6 1.2 7.6 0.5 13.5 0 9.5 0 2.1 0 5.6 8.1 6.4 4.7 4.0 17.7 3.8 3.0 2.4 13.0

13. Patterns of 2 nd -line Drug Resistance in MDR Isolates By Year Of Test (%) 20002001200220032004 Number tested, Total=3,4612943195125201,816 AG+CM AG+FQ AG+ >1 Group 4 drug CM+FQ CM+ >1 Group 4 drug FQ+ >1 Group 4 drug AG+CM+FQ AG+CM+ >1 Group 4 drug AG+CM+FQ + >1 Group 4 Any 3 SLD classes 5.4 4.8 5.8 0.3 1.4 4.4 0.3 1.4 0.3 4.4 3.4 4.4 7.2 1.6 0.9 7.5 1.6 0.9 0.3 6.0 11.9 2.3 9.8 1.0 5.3 4.1 1.0 5.3 0.6 7.6 8.3 5.4 7.5 2.3 3.8 7.7 1.9 3.3 1.3 7.7 6.5 7.9 7.4 4.6 16.2 3.7 3.6 2.5 12.8

14. Limitations Variation in methods and results for SLD testing –No standards for QA for SLD susceptibility testing –Limited reproducibility of DST for certain drugs Sampling bias –Convenience sample does not represent a specific geographic region or patient population –No true denominator; not possible to determine case rates, only case counts –Differing indications for SLD testing (all patients, failures/retreatment cases, only MDR isolates) Different and minimal patient data available to each SRL limited comparisons

15. Conclusions and Recommendations Extremely drug-resistant “XDR” TB has emerged in all continents XDR strains may be –More prevalent in regions with high rates of MDR TB –Increasing over time Imperative to prevent, treat TB & MDR TB more effectively Population-based data needed to estimate current magnitude of XDR TB and monitor trends QC/QA standards for 2 nd -line DST needed to help ensure global reproducibility

16. Next Steps SRLs that agreed to participate but have not yet sent data or only part of data (< 5 years) please send data a.s.a.p. Finalize analysis, draft manuscript, rapid submission Prepare advocacy, publicity strategy Plan population-based survey and/or prospective study